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Mental health edited > Antidepressants > Flashcards

Antidepressants Flashcards

1
Q

What is the goal of antidepressants?

A

Most antidepressants aim to increase the amount of monoamine neurotransmitters in the brain

Serotonin, noradrenaline, adrenaline, dopamine

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2
Q

What are antidepressants used for?

A

Extensive uses in psychiatry

  • Depressive disorders
  • Anxiety disorders
  • PTSD
  • OCD
  • Bulimia nervosa
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3
Q

When are antidepressants most effecive?

A

Antidepressants are generally more effective in those with moderate to severe symptoms

A response is defined in research as a reduction in symptoms of 50%

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4
Q

What is the prognosis in depression overall including different outcomes?

A

Depression Prognosis

  • 20% recover without treatment
  • 30% recover with placebo
  • 50% recover with antidepressants
  • 10-30% show treatment resistance
  • Antidepressants have a NNT of 3 compared to no treatment
  • And an NNT of 5 compared to placebo
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5
Q

What is the NICE stepped care model in depression treatment? When does referral to HTT/CRT take place?

A

Step I – Assessment, active monitoring, support, psychoeducation, self-help •

Step II – Low level psychological interventions +/- medication

Step III – Medication and high level psychological interventions

Step IV – Consider the addition of Electroconvulsive Therapy (ECT)

Referral to CRT/HTT can occur in steps I and II based on risk

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6
Q

Which medication is first line antidepressant for depression?

A

SSRIs are recommended as first line medications by NICE due to their tolerability and efficacy

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7
Q

What treatment options are available for treatment resistant depression? What trial guides this?

A
  • Combining antidepressants (e.g. Mirtazapine + Venlafaxine a.k.a California Rocket Fuel)
  • Augmentation with a mood stabiliser (lithium or lamotrigine) or an antipsychotic
  • Ketamine/Esketamine (currently lots of research into psychedelics at Imperial)
  • ECT • Transcranial magnetic stimulation
  • Adding thyroxine/T3 (rarely used)

2006 STAR*D Trial mainly informs this

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8
Q

List some types of antidepressants.

A

Not an exhaustive list as many drugs are available on the market

  • Selective serotonin reuptake inhibitors (SSRIs) – Citalopram, Escitalopram, Sertraline, Fluoxetine, Paroxetine
  • Serotonin and noradrenaline reuptake inhibitors (SNRIs) – Venlafaxine, Duloxetine
  • Noradrenergic and specific serotonergic antidepressants (NASSA) - Mirtazapine
  • Serotonin antagonist/reuptake inhibitors (SARIs) - Trazadone
  • Monoamine oxidase inhibitors (MAOI) - Phenelzine, Tranylcypromine, Moclobemide and Isocarboxazid
  • Tricyclic antidepressants (TCAs) - Clomipramine, Imipramine, Amitriptyline, Nortriptyline, Dothiepin (dosulepin) - mostly used nowadays for neuropathic pain
  • Others – Vortioxetine (Mixed 5HT agonist and antagonist), Agomelatine (M1 and M2 Melatonin receptor agonist)
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9
Q

What is seritonin?

A

5HT

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10
Q

Describe the synthesis of serotonin.

A

Synthesis begins with tryptophan.

Tryptophan hydroxylase (TRY-OH) converts tryptophan into 5 hydroxtryptophan.

Then, aromatic amino acid decarboxylase (AAADC) converts 5 hydroxtryptophan into 5HT

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11
Q

Once 5HT is synthesised where is it taken up?

A

After synthesis 5HT is taken up into synaptic vesicles by a vesicular monoamine transporter (VMAT2) and stored until needed

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12
Q

Where do serotonin neurons mostly originate?

A

Serotonin neurons mostly originate in the raphe nuclei of the brain stem

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13
Q

What inactivated 5HT in the brain?

A

5HT action is terminated by the enzyme monoamine oxidase (MAO)

MAO-A is found outside neurons and has a strong affinity for 5HT

MAO-B is present inside neurons and has much a lower affinity, therefore

MAO-A is the more important enzyme for inactivating 5HT

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14
Q

How is serotonin recycled?

A

5HT is also recycled via the serotonin reuptake transporter (SERT).

This pumps 5HT back into the pre-synaptic neuron so it can be stored and used again

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15
Q

Give examples of SSRIs.

A

Main examples include Citalopram, Escitalopram, Sertraline, Fluoxetine, Paroxetine

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16
Q

What are the side effects of SSRIs?

A

Nausea and vomiting (due to large number of serotonin neurons in the gut)

Sexual side effects (anorgasmia, delayed ejaculation). Short acting SSRI Dapoxetine used to treat premature ejaculation. Sexual side effects also a feature of depressive illnesses! This can cause confusion

QTc prolongation with citalopram

Increased suicidality when starting SSRIs in those under 25

Hyponatraemia

Increased risk of bleeding with SSRIs – Reduction of serotonin in platelets (caution in those with history of GI bleeds)

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17
Q

Which SSRI is the only one which causes QTc prolongations?

A

Citalopram

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18
Q

What is the MOA of SSRIs.

A

All SSRIs stop serotonin reuptake by inhibiting the serotonin reuptake transporter (SERT) (to about 80% receptor occupancy BUT this isn’t the full story…

Increased serotonin in the synaptic cleft by SERT inhibition causes the overstimulation of 5HT-1A autoreceptors

This causes them to downregulate and become desensitised due to chronic over stimulation (mediated by altering gene expression)

Once the 5HT-1A autoreceptors are downregulated, 5HT can no longer turn off its own release. The serotonin neuron is therefore disinhibited. This results in a flurry of 5HT release from axons

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19
Q

Give 2 examples of SNRIs.

A

Examples include Venlafaxine and Duloxetine

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20
Q

What is the MOA of SNRIs?

A

SNRIs combine robust SERT inhibition with inhibition of the noradrenaline reuptake transporter (NET)

Generally, occupancy of 80-90% at SERT is needed for clinical effect and 50% at NET

NET antagonist has downstream effects on increase dopamine in the PFC, therefore SNRIs act on three monoamine systems

There are very few dopamine reuptake transporters (DATs) located in the prefrontal cortex, so dopamine often diffuses away from the synapse and gets taken up by NET due to chemical similarity of dopamine and noradrenaline

21
Q

What is an example of a NASSA?

A

Mirtazapine

22
Q

What is the moa of NASSAs?

A
  • An alpha 2 receptor antagonist
  • This is a pre-synaptic receptor and functions as an autoreceptor
  • Mirtazapine interacts with alpha 2 receptors on both serotonin and noradrenaline neurons
  • Noradrenaline turns off its own release by binding with pre-synaptic alpha 2 autoreceptors. Antagonism of these autoreceptors leads to disinhibition of noradrenergic neurons and an increase in noradrenaline release
23
Q

What is a side-effect of a NASSA? What receptor is involved? Is this sometimes helpful?

A

Mirtazapine blocks the H1

Leads to sedation and increased appetite

This can make it helpful for poor sleep but it can lead to weight gain

24
Q

Why are TCAs tricyclic? What are some examples? What are they most commonly used for nowadays?

A

Named because their chemical structure contains three rings

Clomipramine, Imipramine, Amitriptyline, Nortriptyline, Dothiepin (dosulepin).

More commonly used these days to treat neuropathic pain at lower doses than are use for depression. But about x10 higher dose is used in depression.

25
Q

What is the MOA of TCAs?

A

All TCAs block the reuptake of noradrenaline via NET inhibition.

All TCAs are also antagonists at H1, alpha 1, M1 cholinergic receptors and also block voltage sensitive sodium channels

Some TCAs are also potent inhibitors of SERT (e.g. clomipramine) and some may also act as antagonists at 5HT-2A and 5HT-2C receptors

This wide receptor binding explains their extensive side effect profile

26
Q

What are the side effects of TCAs?

A

Effective agents but limited as many SE

Most SEs mediated through:

  • H1 (sedation, weight gain),
  • M1 (dry mouth, blurred vision, urinary retention, constipation),
  • alpha 1 (hypotension, dizziness) and
  • voltage gated sodium channel blockade (coma, seizures, heart arrhythmias when used in overdose).

As well as their unpleasant side effect profile, their risk in overdose means their use is strictly as second line agents

27
Q

What are the ECG changes in TCAs?

A

ECG changes include prolongation of the PR, QRS and QT intervals, nonspecific ST segment and T wave changes, atrioventricular block, right axis deviation

28
Q

What are the two types of MOAIs? What is a common use?

A

MAO exists in two subtypes known as A and B. The A form preferentially metabolises the monoamines most commonly linked to depression (i.e. serotonin and noradrenaline)

Inhibiting MAO-B is primarily used in raising dopamine levels in those receiving levodopa treatment for Parkinson’s disease

29
Q

What is the MOA of some MAOIs?

A

Phenelzine, Tranylcypromine and Isocarboxazid are all irreversible enzyme inhibitors. Normal enzyme activity only returns 2-3 weeks later when new enzyme has been synthesised

Moclobemide binds reversibly to MAO-A and therefore it is always competing with native enzyme

30
Q

What is the ‘cheese reaction’? How does it occur? What is the prevention method?

A

Also known as the dietary tyramine interaction

Taking a MAOI + consuming tyramine in diet = risk of developing a hypertensive crisis

Tyramine acts as a catecholamine releasing agent. Normally the release of noradrenaline by tyramine is inconsequential as MAO-A destroys it. In the presence of an MAO-A inhibitor noradrenaline can lead to a significant rise in blood pressure

A person normally can metabolise 400mg of tyramine per day and even a high tyramine diet typically contains less than 40mg. When an MAO-A inhibitor is present it may take as little as 10mg to increase blood pressure

Patients advised to have a low tyramine diet. Mostly avoid fermented or aged foods

31
Q

What are the foods to avoid with MAOIs? Which foods are safe?

A
32
Q

What is seritonin syndrome? Who should you suspect it in? What non-SSRI can increase risk?

A

Potentially life threatening complication = in essence is serotonin toxicity

Suspect in those taking high dose antidepressants or multiple antidepressants

People taking multiple antidepressants are a risk, especially those taking MAOIs and TCAs

Tramadol also has serotonergic activity and can increase risk

33
Q

How is serotonin syndrome diagnosed?

A

A clinical diagnosis; no tests are available

34
Q

What are the mild symptoms of serotonin syndrome?

A

Mild – Insomnia, anxiety, nausea, diarrhoea, hypertension, hyper-reflexia

35
Q

What are the moderate signs and symptoms of serotonin syndrome?

A

Moderate – Agitation, myoclonus, tremor, mydriasis, diaphoresis, low grade fever (38.5 degrees),

36
Q

What are the severe symptoms of serotonin syndrome?

A

Severe – Hyperthermia (>38.5 degrees),confusion, rigidity, respiratory failure, coma, death

N.B – Key take home symptoms. Altered mental status, sweating, fever and hyperreflexia/clonus (they look like a melting snowman!)

37
Q

What is the management of serotonin syndrome?

A

Management – Stop antidepressants. Fluids and supportive care. Symptoms typically resolve in 24 hours

38
Q

What happens when you stop antidepressants?

A

All antidepressants have the potential to cause a withdrawal syndrome, especially if taken for >6 weeks

Abrupt cessation should be avoided to avoid symptoms

39
Q

Which two antidepressants have the most severe withdrawal symptoms? What property does this depend on?

A

Venlafaxine and Paroxetine are associated with the great withdrawal symptoms

Drugs with longer half lives (e.g. Fluoxetine with a half life of 4-6 days) generally are less likely to cause withdrawa

40
Q

What are the symptoms of antidepressant withdrawal?

A
  • Restlessness,
  • sweating,
  • electric shock sensations in the scalp,
  • insomnia,
  • GI upset.
  • Often described as “flu like symptoms”
41
Q

What is the prognosis with antidepressant withdrawal? What is the management of antidepressant withdrawal? How do you prevent it?

A

Symptoms are not dangerous, generally mild and last for 1-2 weeks

Aim to taper over 2-4 weeks to avoid withdrawal - Maudsley Prescribing Guidelines has advice on how to cross taper from one antidepressant to another

42
Q

What is St John’s Wort? What is the MOA?

A

A popular name for the plant Hypericum Perforatum

Can be bought over the counter as a herbal preparation with reported beneficial effects on mood

Mechanism poorly understood but it may inhibit MAO and inhibit the SERT and NET in addition to affecting serotonin receptor expression

43
Q

Why is St John’s Wort use not recommended by doctors?

A

It’s efficacy in depression is unclear and it should not be recommended

  • Is associated with an increased risk of bleeding like SSRIs
  • Potent hepatic enzyme inducer. Reduces plasma levels of warfarin, hormonal contraceptives and digoxin
  • It’s use may also contribute to the risk of serotonin syndrome in those taking other antidepressants
44
Q

How long do antidepressants take to work?

A

Generally 2-6 weeks due to their mechanisms of action often working through altering gene expression

45
Q

Are antidepressants addictive?

A

No, they do not change dopamine levels in the mesolimbic reward pathway

46
Q

How long should treatment with antidepressants continue?

A

Depends on the nature of the illness and risk

Rule of thumb: Continue for 6-9 months following resolution of the episode of illness

47
Q

Why do you need to monitor antidepressants especially in the young?

A

Review regularly (i.e. weekly) when starting antidepressants in the young due to the theoretical increased risk of suicidality

48
Q

Can antidepressants cause mania?

A

They can precipitate hypomanic episodes in those with an underlying bipolar illness

The first line treatment for bipolar depression is mood stabilisers not antidepressants

Mental health edited (53 decks)

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